Obesity affects 31% of adults and leads to devastating and costly health problems and reduces life expectancy. There are however, no current effective drug treatments for obesity. Support for basic science research has led to the discovery of a number of new chemical signals and their receptors that contribute to energy balance control. Those discoveries have driven the development of new drugs that are in the pipeline as obesity treatments. It is clear however, that energy balance control is multi-determined; with multiple signals, receptors, and regions of the brain operating with some degree of redundancy to insure that adequate energy is available to power cellular processes required for survival and reproduction. For this reason, it is important to be skeptical about whether emerging treatments will be efficacious in treating obesity. It would seem that more progress in defining drug targets for effective obesity treatment would be obtained, if the field were to examine the neurochemical phenotypes and receptors of neurons that are common to the intake inhibitory effects of different physiological signals. To this end, this proposal seeks to define the neurons, mechanisms of action, intracellular signaling pathways and receptors that mediate the combined intake reducing effects of two, different and important signals: the adiposity hormone leptin and gastrointestinal (GI) satiation signals. Although these two signals are known to interact in control of food intake, virtually nothing is known about the signaling pathway that mediates their interaction and which of the various leptin receptor-bearing neurons contributes to the potentiation of the intake reducing effect of GI satiating signals. A set of novel experiments is proposed and innovative methods are employed. Aim I probes the functional role of leptin signaling in two anatomically distributed nuclei: the nucleus tractus solitarius of the caudal brainstem and the arcuate nucleus of the hypothalamus (via targeted brain injections of leptin, a novel leptin receptor antagonist, and RNA interference knockdown of leptin receptors in these two regions) on the intake suppressive effects of gastric distension and intraintestinal nutrient delivery. Aim II explores whether the fuel sensing enzyme, adenosine monophosphate-activated protein kinase (AMPK), acts as a common intracellular signal that mediates the potentiation of the intake inhibition of GI signals by leptin and whether local, biochemically induced changes in AMPK activity drive direction-appropriate adjustments in food intake and energy expenditure. Aim III examines whether the food intake and energy expenditure effects of leptin and GI satiation signals are mediated by caudal brainstem melanocortin receptors. Aim III also identifies the neurochemical phenotypes of hypothalamic and hindbrain neurons whose activation by GI satiation signals is amplified by leptin. Results of these studies will address important, and as yet, unaddressed basic research questions that will yield a deeper understanding of the molecules and fundamental biological pathways and mechanisms that regulate food intake and energy expenditure. The identification of the neurons commonly activated by leptin and GI satiation signals and their neurochemical phenotypes and the mechanism of interaction between these two important control signals will be helpful in guiding the design of new drugs and perhaps also the development of new paradigms to increase the intake and weight loss effects of drugs that are currently available. Basic scientists make discoveries that suggest that stimulating one brain chemical system will reduce food intake, and then the pharmaceutical industry develops such a drug to treat obesity. The problem with this approach, and the drugs now on the market, is that the control of food intake is so important for survival that many separate chemical systems work in parallel to insure that food intake is not reduced. A novel approach is taken here; we think that more progress in finding effective drug treatments would arise from defining the brain chemical systems that are commonly activated by food in the gut (stomach and intestine) and by the hormone leptin, as food intake is more effectively reduced by their combination.